The success of clinical transplantation is one of modern medicine's hallmark achievements. Unfortunately, a severe shortage of human organs, cells, and tissues constrains application of this life-saving technology. This RFA recognizes the potential for transplants from another species to humans (xenotransplantation) to fulfill the fields potential. For scientific and ethical reasons, a consensus has formed around discerning how to safely use pig organs for this purpose. Clinical application of pig-to-human xenografts is currently prevented by vigorous immunologic barriers. Major progress has been made over the past two decades to understand and overcome these barriers, with key contributions over the past 9 years from our Program and other NIAID Consortium members. Most importantly, our Program has produced pigs that express a large number of human proteins that each protects the pig organ from injury by the primate immune response. The lung xeno model has been particularly useful to demonstrate the value of each of these modifications, and to identify remaining problems. With a combination of three to six gene modifications to the pig, and a carefully tailored drug treatment regimen to the recipient, current results have advanced from minutes to hours (lung) or days (liver), with more significant progress for kidneys (from weeks to months) and hearts, where survivals past one and even two years have recently been accomplished by members of our consortium. Our proposals in response to the current RFA concentrate attention largely on the residual problem of the inflammatory response to pig organs. We shall explore methods of preventing or suppressing this response through either novel pig genetics or pharmacologic interventions. We will investigate transplantation of organs from these novel pigs, modifications to our already successful immunosuppressive regimen (in an effort to minimize infectious complications), and several anti-inflammatory agents that might allow consistent long-term (>6 months) pig kidney and heart graft survival, while significantly extending survival of livers and lungs. These studies will be carried out in our established kidney (Pittsburgh), heart (NHLBI), liver and lung (Maryland) models, with all of which we have many years' experience and expertise. The outcomes of our studies will be comprehensively evaluated by numerous laboratory assays, with all of which we have experience at one or more of our participating centers. We hypothesize that, within the 5-year funding period, this will enable consideration to be given to clinical trials of pig kidney, heart, and liver transplantation and will improve lung survival markedly.